Lead optimization of a butyrylcholinesterase inhibitor for the treatment of Alzheimer’s disease

Košak, Urban (author), Strašek Benedik, Nika (author), Knez, Damijan (author), Žakelj, Simon (author), Trontelj, Jurij (author), Pišlar, Anja (author), Horvat, Selena (author), Bolje, Aljoša (author), Žnidaršič, Neža (author), Grgurevič, Neža (author), Švara, Tanja (author), Kljun, Jakob (author), Stojan, Jure (author), Gobec, Stanislav (author)

Butyrylcholinesterase (BChE) is a promising drug target for alleviating the symptoms of canine cognitive dysfunction (CCD) and Alzheimer’s disease (AD). We have recently developed lead compound 2, a racemic, nanomolar BChE inhibitor with procognitive effects in mice with scopolamine-induced AD-like symptoms and dogs suffering from CCD. To overcome its modest brain exposure, we developed compound (R)-(−)-3, a more potent BChE inhibitor with a 7-fold higher in vivo brain exposure. It has procognitive effects in mice with scopolamine-induced AD-like symptoms and, superior to compound 2, also in mice with Aβ$_{1−42}$-induced AD-like symptoms. Compound (R)-(−)-3 produces no cholinergic adverse effects or motor deficits and has no acute toxic effects in mice. This makes sulfonamide (R)-(−)-3 an optimized lead compound for alleviating the symptoms of AD.

• Language: English
• Keywords: central nervous system, drug discovery, inhibitors, screening assays, sulfones
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; VF - Veterinary Faculty; FKKT - Faculty of Chemistry and Chemical Technology; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: Str. 11693-11723
• Numbering: Vol. 68, iss. 11
• PID: 20.500.12556/RUL-176545
• UDC: 616.894
• ISSN on article: 1520-4804
• DOI: 10.1021/acs.jmedchem.5c00577
• COBISS.SI-ID: 238259203
• Publication date in RUL: 03.12.2025

Record is a part of a journal

• Title: Journal of medicinal chemistry
• Shortened title: J. med. chem.
• Publisher: American Chemical Society
• ISSN: 1520-4804
• COBISS.SI-ID: 512806681

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: centralni živčni sistem, odkrivanje zdravil, inhibitorji, presejalni testi, sulfoni, Alzheimerjeva bolezen, zdravljenje